Varicella/zoster virus (VZV) is a virtually universal infectious agent. The natural history, pathophysiology and effective therapy of the clinical diseases induced are yet to be elucidated. Varicella is second only to gonorrhea as the most frequently registered infectious disease in the USA. Reactivated "latent" VZV infection, herpes zoster, is a widespread, often debilitating disease especially in the elderly and immunocompromised patient. Of the estimated 300,000 new cases of zoster annually in this country nearly 56,000 involve the eye with more than 50% of patients suffering visual loss as a result of acute or chronic disease. The fundamental problem that has hampered our understanding of the mechanisms and therapy of VZV-induced disease is the lack of either an in vitro or in vivo model of infection that mimics the human ocular or systemic disease. Recent development in our laboratory of guinea pig and rabbit in vitro and in vivo models of VZV infection has allowed an initial characterization of the ocular and systemic disease process. Long range goals of this proposal include study of the acute ocular, systemic and latent VZV infection and reactivation of latent diseases. Standard virologic techniques, indirect immunofluorescence, histopathological, and ultrastructural studies will elucidate the parameters associated with these disease states. In situ nucleic acid hybridization and DNA dot-blot hybridization with a radiolabelled cloned plasmid VZV DNA probe will be used to localize the VZV genome in ocular tissues, trigeminal, superior cervical and thoracic sympathetic chain ganglia, midbrain, and cerebellar specimens. Viral reactivation techniques (indwelling electrode stimulation and/or 6-hydroxydopamine corneal iontophoresis) will be used to study reactivation of latent ganglionic VZV in vivo. Antiviral agents will be evaluated for efficacy against VZV and used to develop a drug-induced suppression model in vitro (guinea pig and rabbit monolayer and trigeminal neuron cultures). In vivo studies will include systemic and topical antiviral therapy of ocular and other VZV infection during the acute disease. Long-term systemic antiviral therapy of acute and late ganglionic VZV infection will be evaluated for effect on foci of latent infection. Non-toxic, specific antiviral drugs (ACV, BVDU) and proacyclovir compounds (BW759U and A515U) will be used in in vivo and in vitro antiviral experiments.